Emerging data suggest that peroxisome proliferator-activated receptor- ? (PPAR-?) is a critical determinant that may provide functional links between diabetes and CVD. During the past cycle of this R01 funding, our laboratory has made a series of significant contributions to better understand the role of PPAR-? activation in the vasculature. The insulin-sensitizing thiazolidinediones (TZDs) are synthetic ligands of PPAR-? and the first drugs used to treat insulin resistance in patients with type 2 diabetes. Despite of their effectiveness as insulin sensitizers and their protective effects in the vasculature, the therapeutic efficacy of TZDs has been severely compromised due to the appearance of associated cardiovascular events. Thus, the investigation of the molecular mechanisms underlying PPAR-? functions especially in the cardiovascular system are of utmost importance. Of significance, we have identified a nitric oxide (NO) and fatty acid-derived product, nitrated derivatives of fatty acids (NO2-FA) including nitrated oleic acid (OA- NO2) and linoleic acid (LNO2), as potent endogenous PPAR ? ligands. More recent analysis by our laboratories clearly documented that NO2-FA-activated PPAR ? recruits/displaces differential cofactors leading to a pattern of gene expression that mediate different biological responses compared to TZD-activated PPAR ?. Also, we have identified Kruppel-like factor 11 (KLF11) as a novel PPAR3 cofactor. Although KLF11 gene mutations cause MODY7, an early-onset type 2 diabetes mellitus, but its role in the vasculature is entirely unknown. Based on these key results, in this proposal we will test the central hypothesis that NO2-FA-modulated PPAR ? activation and the recruitment of KLF11 play a critical role in protecting the vasculature from vascular lesion formation, thereby contributing to maintenance of vascular homeostasis. Specifically, we will 1) Determine the molecular interactions between NO2-FA and PPAR-? in vascular remodeling; 2) Define KLF11 as a novel PPAR-? cofactor required for PPAR-? function during vascular lesion formation. Advances in understanding the mechanisms of endogenous PPAR-? modulation will provide novel therapeutic strategies for treating diabetes and CVD. PUBLIC HEALTH RELEVANCE: Cardiovascular diseases (CVD) are the primary cause of mortality among diabetic patients accounting for almost 2 out of 3 deaths. The insulin-sensitizing thiazolidinediones (TZDs) are synthetic ligands of PPAR-? and the first drugs used to treat insulin resistance in patients with type 2 diabetes. Despite of their effectiveness as insulin sensitizers and their protective effects in the vasculature, the therapeutic efficacy of TZDs has been severely compromised due to the appearance of associated cardiovascular events. This proposal will explore mechanisms how the endogenous PPAR-? ligands, nitro-fatty acids modulate PPAR-? signaling to inhibit vascular lesion formation. The successful implementation of this proposal should lead to a better understanding of endogenous signaling actions of nitro-fatty acids in the vasculature and will provide novel approaches to develop the next generation of PPAR-? drugs with anti-diabetic and anti-CVD properties.